Cerebrospinal Fluid Flow Is Far More Variable Than Doctors Thought

For decades, the cerebrospinal fluid that bathes the brain and spinal cord was treated as a relatively stagnant liquid, a passive cushion whose movements were of little consequence to medicine. That assumption has now collapsed. A sweeping review published in Frontiers in Drug Delivery argues that the circulation of cerebrospinal fluid, or CSF, is astonishingly variable — shaped by everything from the beating of the heart and the rhythm of breathing to the time of day, a person’s posture, their age, and the diseases they carry. The consequences reach far beyond basic physiology: they may determine whether cutting-edge therapies, including gene therapy vectors and macromolecular drugs, actually reach the brain regions they are meant to treat when injected directly into the brain’s ventricles.

The review, led by researchers including Hans Engelhard of AbbVie and the University of Illinois at Chicago, consolidates knowledge from across the published literature to examine why CSF circulation differs so much between healthy individuals and between patients. The timing is significant. A wave of sophisticated therapeutic agents — from antisense oligonucleotides like nusinersen and tofersen to adeno-associated virus (AAV) capsids carrying corrective genes — is being designed for delivery straight into the CSF, circumventing the formidable blood-brain barrier. Understanding how CSF moves, and why its movement varies, is now a practical prerequisite for getting these treatments to work.

At the heart of the matter is a fluid system of remarkable complexity. CSF is produced mainly by the choroid plexus, a frond-like structure within the ventricles, at a rate of roughly 500 millilitres per day in an adult human — yet the entire ventricular system holds only about 25 millilitres, and the total CSF volume of 140 to 200 millilitres is turned over three to four times daily. This constant production must be matched by equally constant resorption, primarily through arachnoid granulations that project into the dural venous sinuses and act as miniature pressure-regulating valves. If production outpaces absorption, pathological ventricular dilation — hydrocephalus — results, and the choroid plexus, stubbornly, keeps producing CSF regardless.

What propels this fluid is not a single pump but a symphony of forces. Each heartbeat sends a pressure wave through the choroid plexus and along the CSF pathways, driving an alternating bidirectional flow: craniocaudal during systole, caudocranial during diastole. Respiratory cycles superimpose their own lower-frequency oscillations. The development of phase-contrast MRI has been revolutionary here, allowing researchers to measure these flows directly in living humans. Before this technique, CSF was considered nearly motionless; now its velocity can be quantified, with peaks approaching 80 centimetres per second in arterial flow and slower but measurable movements in CSF. The technique revealed that CSF oscillations are primarily driven by cerebral arterial flow, with the intracranial subarachnoid space containing the largest CSF volume able to move rapidly into the spinal canal during each cardiac cycle.

The anatomy of the pathways adds another layer of variability. From the lateral ventricles, CSF flows through the foramina of Monroe, the third ventricle, the cerebral aqueduct, and the fourth ventricle before exiting through the foramina of Magendie and Luschka into the cisterna magna and subarachnoid space. These exits could be considered chokepoints of CSF circulation. The human foramen of Magendie is only 2 to 5 millimetres in diameter — yet still roughly 40,000 times larger than an AAV capsid, the viral vector at the centre of many gene therapy programmes. Once in the subarachnoid space, CSF distributes across a three-dimensional network of sulci and cisterns — approximately 40 in humans — compartmentalised by arachnoid membranes such as Liliequist’s membrane. Crucially, these membranes are not universally present across all individuals, a variability that may have significant implications for drug delivery.

Beyond anatomy and pulsations, physiological state exerts profound effects. The circadian cycle increases CSF production by 12 to 20 percent during the dark phase, raising intracranial pressure by roughly 30 percent — a pattern conserved across species despite different activity patterns. Sleep, particularly deeper sleep, increases CSF pulsations and velocities, expected to enhance the glymphatic clearance system that removes waste products from the brain. Posture matters enormously: a rotatable MRI system showed that transitioning from lying to standing changes choroid plexus volume by approximately 7.5 percent, potentially altering production and circulation. Even the depth of breathing measurably changes CSF volume displacement. Sex differences exist as well, with young female mice producing roughly 30 percent more CSF than age-matched males, and human males generally showing more pronounced CSF dynamics than females independent of age.

Age reshapes the entire system. In newborns and children, CSF stroke volume changes rapidly with skull growth. In the elderly, CSF flow becomes more pronounced in the cerebral aqueduct, while choroid plexus volume increases but perfusion decreases, suggesting reduced production. Decreased CSF flow has been linked to cognitive decline in elderly patients and those with neurodegenerative diseases. Advancing age generally opens CSF pathways through brain atrophy, yet within the spine, degenerative changes restrict flow — a divergence with direct dosing implications, since the same drug dose and schedule are typically used across adult clinical trial patients regardless of these variations.

Disease states add further complexity. Obstructive hydrocephalus, whether from tumours, haemorrhage, infection, or congenital malformations, represents the most severe restriction. Normal pressure hydrocephalus presents aqueductal pulsatility over ten times normal levels. Chiari malformation obstructs the foramen magnum, altering pulsations and compliance. Even conditions not traditionally associated with CSF pathology — atrial fibrillation, for instance — have recently been shown to reduce and de-rhythmicise CSF flow, potentially impairing glymphatic waste clearance and explaining the association with dementia. Anaesthesia, too, modulates the system, with different agents producing increased or decreased flow rates depending on their effects on heart rate, blood pressure, and cerebral vascular resistance.

For intraventricular drug delivery, these variables translate directly into dosing considerations. The predominant cranial-to-caudal flow direction makes the intraventricular route superior to lumbar intrathecal injection for reaching the brain, particularly structures like the basal ganglia that lie close to CSF pathways. Catheter placement — frontal versus occipital trajectories — influences distribution to different brain regions. Increased CSF flow increases ventricular flushing and decreases drug contact time with ventricular walls, a critical first step before parenchymal penetration. Factors affecting microcirculation, such as ciliary integrity, affect local mixing and adherence. The ependymal lining, a single layer of multi-ciliated cells with adherens and gap junctions, is far more permeable than the blood-brain barrier — providing the rationale for intraventricular administration of large molecules and vectors.

The review’s authors propose that the most significant factors causing variability of CSF macrocirculation — and thus intraventricular drug delivery — are overall CSF production, anatomical pathway variation, and age. They advocate for personalised tracer assessment, using PET-labelled antibodies or AAV capsids to track biodistribution noninvasively in individual patients, and suggest that phase-contrast MRI could be decisive for determining clinical trial eligibility. Recent human data showed that a radiolabeled monoclonal antibody injected into the ventricles distributed throughout the cranial and spinal subarachnoid space within four hours and over the cerebral convexities within 24 hours. As gene therapies for Alzheimer’s, Parkinson’s, Huntington’s, ALS, and dozens of rare metabolic diseases advance toward the clinic, the review’s central message is clear: the dosage and scheduling of intraventricular therapies must be tailored to individual patient characteristics — including factors as seemingly minor as body position or time of day — if these sophisticated treatments are to harness, rather than be defeated by, the remarkable variability of the brain’s own plumbing.

Subject of Research: Neuroscience

Article Title: Variability in the circulation of cerebrospinal fluid: causes and clinical implications for intraventricular drug delivery

Article References: Engelhard, H. H., Balédent, O., Borzage, M. T., Andrews-Jones, L., Feldsien, T. M., & Lefebvre, D. R. (2026). Variability in the circulation of cerebrospinal fluid: causes and clinical implications for intraventricular drug delivery. Frontiers in Drug Delivery, 6, Article 1735474. https://doi.org/10.3389/fddev.2026.1735474

Image Credits: AI Generated

DOI: 10.3389/fddev.2026.1735474

Keywords: Variability, circulation, cerebrospinal, fluid, causes, clinical, implications, intraventricular, drug, delivery, scientific research